Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 10, Issue 1, 2010

With this first issue of the year, Central Nervous System Agents in Medicinal Chemistry continues with its objective of bringing together the different perspectives of scientists with diverse backgrounds in chemistry, biology and pharmacology with the common goal of fostering the development of medicinal chemistry. With a careful selection of subjects and up to date reviews, Central Nervous System Agents in Medicinal Chemistry intends to remain as the reference journal in the area of medicinal chemistry reviews and to keep its upfront position with growing scope and impact in current science. The study of the central nervous system has represented a continuous challenge in science. Nowadays, the great efforts carried out by a generation of brilliant scientists have enabled to discover the main mechanisms involved in neurotransmission, making their pharmacological regulation possible in a number of cases. However, a lot of challenges remain; in particular, therapies which face neurodegenerative diseases, molecular mechanisms involved in neurogenesis, and the interaction between nervous and immune system. In this context, this issue reviews the state-of-art of established and novel therapeutic strategies for the treatment of some of the neurodegenerative diseases with the highest prevalence. It also describes the current situation and therapeutic applications of neuronal regeneration and neurogenesis as well as the relationship between immune and nervous systems. This issue contains seven reviews contributed by leading experts in the field. Drs. R. Ehling, T. Berger and M. Reindl review the current situation of novel therapeutic approaches based on targeting multiple sclerosis disease pathway at different points whereas Dr. P. Taupin discusses how oxidative stress affects to the pathology of Alzheimer disease. More focused on the role of proteoglycans, Dr. N. Maeda examines the role of the structural variations of chondroitin sulphate in the central nervous system. Drs. T.F. Dijkmans, L.W.A. van Hooijdonk, C.P. Fitzsimons and E. Vreugdenhil review the current knowledge on the role of the doublecortin gene family in disorders of the central nervous system. Moving on to the interaction between nervous and immune system, Drs. J.R. Rivers and J.C. Ashton discuss the applications of CB2 agonists in different neurological conditions with a focus on microglia. Progressing on this line, Drs. R. Pacheco, E. Riquelme and A.M. Kalergis review the emerging role of neurotransmitters as regulators of several immune cell responses, with special attention to dendritic and T cells. Finally, Drs. R. Bartzatt, S.L.G. Cirillo and J.D. Cirillo offer a current perspective on the application of sulphonamide-based antibiotics for the treatment of MRSA and MSSA infections of the central nervous system.

Multiple sclerosis (MS) is the most common disabling neurological disease in young adults characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal pathology within the central nervous system. Currently approved disease-modifying treatments achieve their effects primarily by blocking the proinflammatory response in a nonspecific manner. Their limited clinical efficacy urges a more differentiated and specific therapeutic approach. Advances in understanding the pathophysiology of MS and appreciation of the contribution of neurodegenerative processes to disease pathology have led to promising therapeutic approaches at different points along the MS disease pathway: (i) monoclonal antibody therapy has provided the opportunity to rationally direct the therapeutic intervention by specifically targeting mechanisms of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab); (ii) novel oral immunomodulating agents have shown to prevent lymphocyte recirculation from lymphoid organs such as fingolimod (FTY720); (iii) blocking of intracellular signaling cascades or ion channels at the cell-surface can protect axons from degeneration and restore axonal function in experimental settings; (iv) neuroprotective agents and stem cell therapy are able to promote remyelination and axonal regeneration in vitro. Despite the tremendous efforts undertaken, a better understanding of the sequential evolution of the MS lesion and the development of clinical surrogate markers, which allow to define subsets of patients with different forms of underlying pathogenesis, is necessary. This will pave the way for an optimized treatment approach, which will likely need both to target inflammation and to focus on promotion of neuroprotection and repair.

Oxidative stress is a deleterious condition leading to cellular death. It plays a key role in the development and pathology of neurodegenerative diseases, like Alzheimer's disease (AD). AD is the most common form of dementia among elderly. Genetic mutations and genetic, acquired and environmental risk factors, particularly neuroinflammation and oxidative stress, are the main causes of AD. Neurogenesis occurs in the adult brain of mammals, particularly in the hippocampus, and is enhanced in the brain of patients with AD. Enhanced neurogenesis in AD may represent an attempt by the central nervous system to compensate for the neuronal loss and repair itself. Reactive oxygen species (ROS) promote cell death and the nondisjunction of chromosomes, leading to aneuploidy. The activity of ROS on newly generated neuronal cells in the adult brain may contribute to the pathogenesis of AD. Antioxidant may be used to reduce the deleterious activity of ROS, particularly on newly generated neuronal cells of the adult brain, potentially delaying the development of AD and promoting the regenerative capacity of the adult brain.

Chondroitin sulfate is popular in the field of neuroscience, because the treatment of nervous tissues with chondroitinase ABC, which degrades chondroitin sulfate up to unsaturated disaccharides, causes severe changes in various aspects of neural development and functions. Chondroitinase ABC treatments of developing nervous tissue impair the growth and differentiation of neural progenitor cells, and cause various pathfinding errors of axons. After injury to the adult central nervous system, axon regeneration fails at scar regions expressing large amounts of chondroitin sulfate proteoglycans. However, after chondroitinase ABC treatment, many axons regenerate and traverse the damaged areas. Furthermore, it was revealed that chondroitin sulfate proteoglycans are involved in neural plasticity. These observations indicated that chondroitin sulfate proteoglycans as major components of the extracellular matrix and cell surface play pivotal roles in the development, regeneration, and plasticity of neuronal networks. Chondroitin sulfate shows highly diverse structural variation, and recent studies indicated that this glycosaminoglycan binds with various growth factors, chemokines and axon guidance molecules in a structure-dependent manner and regulates their activities. Notably, oversulfated structures such as D (GlcA(2-O-sulfate)β1-3GalNAc(6-O-sulfate)) and E (GlcAβ1-3GalNAc(4,6-O-disulfate)) units constitute the binding sites for many proteins, and play important roles in regulation of the growth of neural progenitors, neurite extension, and neuronal migration. The synthesis of these structures is strictly regulated by the chondroitin sulfate synthase family and many sulfotransferases, which should be useful therapeutic targets in neurological disorders.

The doublecortin gene family is associated with subcortical band heterotopia, lissencephaly, epilepsy, developmental dyslexia and retinitis pigmentosa. At least 11 genes homologous to the doublecortin gene exist in humans and mice. Cellular processes regulated by different members of the doublecortin family involve neuronal migration, neurogenesis and eye receptor development. Underlying mechanisms include regulation of cytoskeletal structure and microtubule- based transport. Through their doublecortin-domains, doublecortin proteins can bind microtubules and regulate microtubule- dependent processes. However, this regulation is complex and involves many interacting proteins. Moreover, different spatiotemporal expression patterns and the generation of splice variants further contribute to this complexity. The doublecortin-like kinase 1 gene in particular, produces splice variants with different protein domains such as doublecortindomains, a serine, threonine and proline-rich domain and a serine/threonine kinase-domain. Here, we review our current knowledge on the doublecortin gene family with an emphasis on proteins interacting with doublecortin domains and other domains. In addition, to generate new hypotheses for further research, we analyzed the serine, threonine and proline-rich domain for predicted protein interactions.

Two cannabinoids receptors have been characterised in mammals; cannabinoid receptor type 1 (CBI) which is ubiquitous in the central nervous system (CNS), and cannabinoid receptor type 2 (CBII) that is expressed mainly in immune cells. Cannabinoids have been used in the treatment of nausea and emesis, anorexia and cachexia, tremor and pain associated with multiple sclerosis. These treatments are limited by the psychoactive side-effects of CBI activation. Recently CBII has been described within the CNS, both in microglia and neuronal progenitor cells (NPCs), but with few exceptions, not by neurons within the CNS. This has suggested that CBII agonists could have potential to treat various conditions without psycho-activity. This article reviews the potential for CBII agonists as treatments for neurological conditions, with a focus on microglia and NPCs as drug targets. We first discuss the role of microglia in the healthy brain, and then the role of microglia in chronic neuroinflammatory disorders, including Alzheimer' s disease and Parkinson' s disease, as well as in neuroinflammation following acute brain injury such as stroke and global hypoxia. As activation of CBII receptor on microglia results in suppression of the proliferation and activation of microglia, there is potential for the antiinflammatory properties of CBII agonist to treat neuropathologies that involve heightened microglia activity. In addition, activating CBII receptors may result in an increase in proliferation and affect migration of NPCs. Therefore, it is possible that CBII agonists may assist in the treatment of neuropathologies by increasing neurogenesis. In the second part of the article, we review the state of development of CBII selective drugs with an emphasis on critical aspects of CBII agonist structural activity relationship (SAR).

Dendritic cells (DCs) are responsible of priming T cells and promoting their differentiation from naive T cells into appropriate effector cells. Each different phenotype of effector T cells promotes the elimination of a determined kind of pathogen or tumour. Thus, DCs and T cells play critical roles on orchestrating adaptive immune responses against specific threats. Because of their fundamental functions at controlling immunity, DCs and T cells require tight regulatory mechanisms to ensure efficient, but safe, immune responses. Several studies have shown that neurotransmitters, in addition to mediate interactions into the nervous system, can contribute to the modulation of immunity by promoting the communication between nervous and immune systems and in the interaction between different immune cells. Due to the pivotal role that the DC-T cell interaction plays in the development and regulation of adaptive immune responses, it is important to understand how the function of these cells may be regulated by neurotransmitters. Here, we review the emerging role of neurotransmitters as regulators of DC and T cell physiology and also how these molecules, by acting on the DC-T cell interaction, may modulate the fate of T cells and, therefore, the nature of the adaptive immune response. Moreover, we discuss how alterations on the neurotransmitter-mediated immune regulatory mechanisms can contribute to the onset of immune-related disorders. In addition, we discuss potential new targets for the design of strategies for therapies against tumours, autoimmunity and neuro-immune related diseases.

For drugs that target the central nervous system (CNS) the penetration of the blood-brain barrier (BBB) is a necessity, whereas for other drugs it is an unwanted side-effect. Infections by Staphylococcus aureus (SA) of the CNS causes brain abscesses and inflammation of the tissue enclosing the brain and spinal cord. In this study four sulfonamide agents are compared to streptomycin for growth inhibition of SA bacteria in vitro. All sulfonamide agents were synthesized using microwave irradiation techniques. All drugs tested show substantial growth inhibition of MRSA and MSSA types of Staphylococcus aureus. Important pharmacological properties of streptomycin and sulfonamide drugs are determined to evaluate the efficacy for CNS targeting in clinical treatment of MSSA and and MRSA infections. Although streptomycin demonstrated considerable inhibition of MSSA and MRSA bacteria, the Log P value of -5.28 and polar surface area (PSA) of 331.4 Angstroms2 effectively inhibits its penetration into the CNS. The Log BB for streptomycin at - 4.756 also indicates a very unlikely candidate to treat SA infections of the CNS. All sulfonamide agents showed significant growth inhibition of MRSA and MSSA while having useful values of Log P and PSA for penetrating the BBB. In addition the Log BB values for each sulfonamide agent indicates these agents will enter the CNS to halt SA infections. The Log BB values for sulfonamide drugs 2, A, B, and C are -1.658, -0.109, -0.109, and -0.243, respectively. Values for Log P were 2.549, 3.27, 3.47, and 2.63, respectively; with PSA values at 137.8 A2, 40.98 A2, 40.98 A2, and 49.36 A2, respectively. The small size of the sulfonamide agents and other physicochemical properties strongly support the contention they can be effectively applied to treat MRSA and MSSA infections of the brain and spinal cord.